1. Field of the Invention
The present invention relates to a biological delivery system loaded with a non-biological material which has a biologically useful effect.
2. Background of the Related Art
The incorporation of chemicals and certain elements into artificial structures for insertion into a host has long been of interest to members of the medical profession. For example, WO 85/00751 discloses the loading of drugs into liposomes (artificial phospholipid vesicles). WO 85/00751 also discloses that the liposomes can be targeted to specific cells by the incorporation of antibodies to antigens known to be associted with the target cell surface. However, since liposomes are not natural structures, they are subject to certain problems such as immunological rejection. Further, liposomes cannot carry a substantial load and tend to have short storage lives.
Another problem is that liposome-entrapped materials tend to leak when the liposome is placed in contact with body fluids. The liposomes also tend to degrade after contacting body fluids and the liposome contents are released in a short period of time. Further, if a very stable liposome is used in vivo, then the liposomal contents will not be released as needed. As a result, stable liposomes tend to be ineffective carriers of therapeutic substances in vivo.
An additional drawback is that liposomes are internalized by naturally occurring phagocytic cells of the reticuloendothelial system (RES), and, therefore, are rapidly cleared from the system. Accordingly, the entrapped drug is largely ineffective against diseases involving cells other than those associated within the RES. A difficulty inherent in treating cells of the RES is that since the cells of the RES phagocytose liposomes, the liposome (and the drugs entrapped therein) are packaged within lysosomes of the phagocytic cell. Very often the lysosome will contain degradative enzymes which will degrade the entrapped compound or render the entrapped compound inactive.
Attempts have been made to overcome the shortcomings inherent in the use of liposomes for targeted drug delivery. For example, International Application WO 85/00751 discloses a process for the preparation of monophasic lipid vesicles (MPVs). MPVs are lipid vesicles which have a plurality of bilayers. An MPV can encapsulate one or more bioactive agents and can be used in vivo in the treatment of disease. Also, U.S. Pat. No. 4,610,868 to Fountain, et al. discloses lipid matrix carriers which provide for the sustained release of bioactive agents in vivo. Drugs, immunoglobulins or other biological materials may be entrapped within the lipid matrix carder. A disadvantage associated with such lipid vesicle structures is that the lipid structures are not native to the host organism and, therefore, they are subject to immunological rejection.
Efforts have been made to incorporate therapeutic substances into non-lipid structures. For example, U.S. Pat. No. 4,671,954 to Goldberg, et al. discloses hydrophilic protein or polypeptide microspheres for incorporation of therapeutic substances. The microspheres are prepared by dispersing an aqueous solution or dispersion of protein or polypeptide in an organic solvent solution of a high molecular weight polymer to form a stabilized dispersion of microspheres. The microspheres are cross-linked with a polyfunctional cross-linking agent. Proteins, antibodies, enzymes, immunostimulants and other compounds may be covalently attached to the microspheres. The microspheres may be targeted to specific tissues using biospecific affinity ligands and may be loaded with biologically active agents. However, being that the microspheres are foreign to the host, the problem of immunological rejection still exists.
Attempts have also been made to enclose paramagnetic materials into artificial lipid structures for use in nuclear magnetic resonance imaging. For example, U.S. Pat. No. 4,728,575 to Gamble, et al. discloses the use of micellular particles to enhance nuclear magnetic resonance imaging by the enclosure of a paramagnetic material within micellular particles such as phospholipid vesicles. To provide specific targeting, antibodies or other cell recognition targeting agents are attached to the surface of the vesicles. A problem with the micellular particles of Gamble, et at. is that they cannot enclose large amounts of paramagnetic materials and are subject to immunological rejection.
Meldrum, et al. (Synthesis of Inorganic Nanophase Materials in Supramolecular Protein Cages, Nature, Vol. 349, 684-687) disclose the use of an apoferritin molecule to form a supramolecular protein cage for the synthesis of inorganic materials in the nanometer dimension. These supramolecular cages are predicted to find applications in catalyses and electro-optical devices. Meldrum, et al. do not relate to or suggest the use of apoferritin in a biological delivery system.
It is, therefore, a desired purpose of the present invention to provide a biostructure having a bioencapsulated non-biological material whose in vivo lifetime and fate are largely determined by the biostructure rather than the material transported therein.
It is a further purpose of the present invention to provide biostructures which have been loaded with a desired non-biological material and which can be introduced into a living system while avoiding any unwanted immune response.
It is yet a further purpose of the present invention to provide biostructures which have been loaded with a toxic non-biological material and which can be introduced into a living system while avoiding or lowering the toxicity of the non-biological material.
It is yet another desired purpose of the present invention to provide a biological delivery system of non-biological materials which can be targeted to predetermined sites within a host.
It is a still further purpose of the present invention to provide a biological delivery system which can provide large amounts of a non-biological material, which has a biologically useful effect, to preselected cells and/or organs.